Antimicrobial compositions comprising dithiocarbamic acid derivatives and method of use



United States Patent ()fiice 3,284,291 Patented Nov. 8, 1966 3,284,291ANTIMICROBIAL COMPOSITIONS COMPRISING DITHIOCARBAMIC ACID DERIVATIVESAND METHOD OF USE Ranajit 'Ghosh, Brackneil, England, assignor toImperial Chemical Industries Limited, London, England, a corporation ofGreat Britain No Drawing. Original application Aug. 20, 1962, Ser. No.218,149, now Patent No. 3,232,974, dated Feb. 1, 1966. Divided and thisapplication Aug. 7, 1964, Ser. No. 394,095 Claims priority, applicationGreat Britain, Aug. 31, 1961, 19,653/ 61 6 Claims. (Cl. 167-30) Thisinvention relates to dith'iocarbamic acid derivatives, to a process fortheir preparation and to antimicrobial compositions containing them.

This application is a division of my copending application, Serial No.218,149, filed August 20, 1962, now US. Patent 3,232,974v

The invention consists in one aspect of antimicrobial compositionscomprising as active ingredient a compound of the formula:

in which R and R are each a hydrogen atom, an aliphatic, aryl or aralkylradical, or R and R together with their adjacent atom constitute aheterocyolic ring; R is an aryl radical; and n is 1, 2, 3 or 4, and acarrier for the said active ingredient.

Where R or R is an aliphatic radical it is preferably a lower aliphaticradical, for example, a methyl, ethyl, propyl or butyl radical; andwhere R and R (together with their adjacent nitrogen atom) constitute aheterocyclic radical it can be, for example, a six-member ring, such aspiperidine, piperazine or morpholine. The grou R is conveniently anunsubstituted phenyl radical, though it can if desired containsubstituents, for example halogen.

The exact form of the antimicrobial composition depends to a largeextent upon the use to which the composition is to be put (-for instanceas foliage fungicide or seed dressing) and the pathogen which it iswished to control. For example, the compositions can be powders,solutions, dispersions or pastes. Where they are powders they can beones in which the active ingredient is in admixture with a powderdiluent. Where the composition is liquid it can be one in which theactive ingredient is dissolved or suspended in a suitable liquid, forexample Water or a suitably non-phytotoxic organic liquid. Theingredients used with the active ingredient in any of the compositionsof this invention can be substances of the type known to the art asbeing suitable in the formulation of antimicrobial compositions, forexample surfaceactive substances such as wetting and dispersing agents,binders, stickers, corrosion inhibitors and stabilising agents.

The invention also consists in dithiocarbamic acid derivatives of theformula shown above. These dithiocarbamic acid derivatives can beobtained, for example, by a process in which a compound of the formula:

is reacted with a suitable salt of a dithiocarbamic acid of the formula:

where R R R and n have the meanings given above and X is a chlorine orlike halogen atom. Suitable salts of the diothiocarbamic acid are thoseof sodium, potassium, ammonium or substituted ammonium.

The invention further consists in a method of combating plant pathogens,in which the foliage of a plant susceptible to such pathogens or seedfrom which the plant can be grown, is treated with 'a compound orantimicrobial composition of this invention. In particularbenzylsulphenyl N:N-dimethyldithiocarfba'mate has been found to have auseful activity when applied as a seed dressing against Xanthomunasmalvaceurwm on cotton.

The invention is illustrated by the following examples:

Example 1 This example describes the preparation of benzylsulphenyl N:N-dimethyldithiocarbamate.

A suspension of sodium N:N-dimethyldithiocarbamate (7.15 g.) in drybenzene (50 cc.) was cooled to about 5 C. and to the cooled suspensionthere was added a quantity of benzylsulphenyl chloride (previouslyobtained from benzyl mercaptan, 6.2 g.) dissolved in benzene cc.). Themixture was stirred at about 5 C. for 15 minutes, then at roomtemperature for 2 /2 hours. After that the mixture was washed with waterand the resulting benzene layer was separated and dried over anhydroussodium sulphate.- The benzene was then removed by distillation and theresidue was recrystallised from ethanol yielding benzylsulphenylNzN-dimethyldit-hiocarbamate as a crystalline solid, M.P. C.

Example 2 Example 3 This example describes the preparation ofbenzylsulphenyl N:N-diethyldithiocarbamate.

A suspension of sodium NzN-diethyl dithioc-arbamate (8.6 g.) in benzenecc.) was stirred and heated under reflux whilst there was slowly runinto it a solution in benzene (60 cc.) of 'benzylsulphenylchloride (pre'viously obtained firorn 6.2g. of benzylmercaptan). After all thebenzylsulphenylchloride had been added, the resu'lting mixture wasrefluxed "for 15 minutes and then allowed to cool to the roomtemperature. The mixture was then washed with water, the resultingbenzene layer was removed and dried over anhydrous sodium sulphate. Onremoval of the benzene by distillation, benzyl sulphenylN:N-diethyldithiocarbamate was obtained as a viscous oil, 11 1.6395.

3 Example 4 This example describes the preparation of benzylsulphenyl Nmethyl-N-phenyldithiocarbamate.

Benzylsulphenylchloride (previously obtained from 6.2 g. of be'nzylmercaptan) was dissolved in dry benzene (50 cc.) and the benzenesolution was gradually added to a boiling suspension of sodiumN-methyl-Nphenyldithiocarbamate (10.3 g.) in dry benzene. Afiter all thebenzylsulphenylchloride had been added the mixture was stirred andrefluxed for 15 minutes, allowed to cool to room temperature and thedesired product of the reaction was isolated from the benzene solutionby the procedure given in Example 1. In this way benzylsulphenylN-methyl-N- phenyldithiocarbam ate was obtained as a crystalline solid,M.P. 85 C.

Example 5 This example describes the preparation of benzylsulphenylN:N-pentamethylenedithiocarbamate.

The procedure of Example 1 was repeated, but using sodiumpentamethylenedithiocarbamate (9.2 g.) instead of the sodiumN:N-dimethyldithiocarbamate of that example.

The product, benzylsulphenyl N:N pentamethylenedithiocarbamate, whenrecrystallised from ethanol was obtained as a crystalline solid, M.P.100 C.

Example 6 This example describes the preparation of benzylsulphenyl N:N-diisopropyldithiocarbam ate.

The procedure of Example 3 was repeated, but using sodiumN:N-diisopropyldithiocarbamate (20g. suspended in 100 cc. benzene) and asolution in benzene (150 cc.) of benzyl sulphenylchloride, previouslyobtained from 12.4 g. benzylmercaptan, instead of the reactants ofExample 3. The product, benzyl sulphenyl NzN-diisopropyldithiocarbamate,when re-crytsallised from ethanol was obtained as a crystalline solid,M.P. 77 C.

Example 7 This example describes the preparation of benzylsulphenylN:N-3-oxapentamethylenedithiocarbamate,

A suspension of sodium 3-oxa-pentanrethylenedithiocarbamate (18.5 g. inbenzene (100 cc.) was stirred and heated under reflux while there wasadded to it a solution in benzene (150 cc.) of benzylsulphenyl chloride(previously obtained from 12.5 g. of benzy-lmercaptan). After refluxingfor two hours, the mixture was cooled and the product was isolatedaccording to the procedure of Example 1. The product was recrystallisedfrom ethanol and benzylsulphenyl 3-oxa-pentamethylene dithiocarbamatewas obtained as a colourless crystalline solid, M.P.

Example 8 This example describes the preparation of bis-benzylsulphenylpiperazine-1,4-bis-carbodithioate.

A suspension of dry sodium piperazine-1,4-bis-lcarbodithioate (14.1 g.)(prepared from piperazine, carbondisulphide and sodium hydroxide) in drybenzene (50 cc.) was cooled to 5 C. and to the cooled mixture there wasadded a quantity of benzylsulphenyl chloride (previously obtained frombenzylmercaptan, 12.4 g.) dissolved in benzene (75 cc.). The reactionmixture was then stirred for /2 hour at 5 C. and then for 2 /2 hours atthe room temperature. The mixture was then filtered and the residue wastreated with water. The water-insoluble residue was collected, dried andrecrystallised from benzene. This gavebis-benzylsulphenylpiperazine-1,4-bis-carbodithioate, M.P. 174 C.

Compounds obtained as products of the examples have been found to showantimicrobial activity against a number of plant pathogens; for exampleas foliage fungicides against Plasmopara viticola, Plzytophthorainfestans, Piricztlarz'a oryzae and Botyrtis fabae. In particular,benzylsulphenyl N:N-dimethyldithiocarbamate obtained as product ofExample 1 has been found to be active in seed dressings against thebacterial disease Xanthomonas malvacearum on cotton.

What I claim is:

1. An antimicrobial composition comprising, as the active ingredient, aneffective amount of a compound of the formula:

in which R; and R are selected from the group consisting of hydrogen,alkyl of up to four carbon atoms, monocyclic carbocyclic aryl and themember which represents the atoms necessary to complete a heterocyclicring with the adjacent nitrogen atom selected from the group consistingof piperidine, piperazine and morpholine; R is monocyclic carbocyclicaryl; and n is an integer from 1 to 4; and a carrier for the said activeingredient.

2. A composition according to claim 1 where the active ingredient is acompound in which n is 1, R and R are lower alkyl and R is phenyl.

3. An antimicrobial composition according to claim 1 wherein the activeingredient is benzylsulphenyl N:N- dimethyldithiocarbamate.

4. A method of combating plant pathogens which cornprises treating thearea subject to said pathogens with a compound of the formula:

in which R and R are selected from the group consisting of hydrogen,alkyl of up to four carbon atoms, monocyclic carbocyclic aryl and themember which represents the atoms necessary to complete a heterocyclicring with the adjacent nitrogen atom selected from the group consistingof piperidine, piperazine and morpholine; R is monocycli-c carbocyclicaryl; and n is an integer from 5. A method of combating Xanthomonasmalvacearum on cotton, which comprises treating cottonseed with acompound of the formula:

References Cited by the Examiner UNITED STATES PATENTS 2,368,515 1/1945Blake 260-247.1 2,792,394 5/1957 Himel et a1 260-247.1 2,897,110 7/1959Scott 167--22 2,911,335 11/1959 Gilbert 167-22 2,941,879 6/1960 Goodhue260247.1 X 2,992,091 7/1962 Harman 7l2.6 3,054,792 9/1962 Howard et al260-247.1 3,070,599 12/1962 Hendry et al 260--247.1

FOREIGN PATENTS 9/1954 Australia.

JULIAN S. LEVITT, Primary Examiner,

GEORGE A. MENTIS, Assistant Examiner.

4. A METHOD OF COMBATING PLANT PATHOGENS WHICH COMPRISES TREATING THEAREA SUBJECT TO SAID PATHOGENS WITH A COMPOUND OF THE FORMULA:R1-N(-R2)-C(=S)-S-S-CNH2N-R3 IN WHICH R1 AND R2 ARE SELECTED FROM THEGROUP CONSISTING OF HYDROGEN, ALKYL OF UP TO FOUR CARBON ATOMS,MONOCYCLIC CARBOCYCLIC ARYL AND THE MEMBER WHICH REPRESENTS THE ATOMSNECESSARY TO COMPLETE A HETEROCYCLIC RING WITH THE ADJACENT NITROGENATOM SELECTED FROM THE GROUP CONSISTING OF PIPERIDINE, PIPERAZINE ANDMORPHOLINE; R3 IS MONOCYCLIC CARBOCYCLIC ARYL; AND N IS AN INTEGER FROM1 TO 4.